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Background: Screening for increased waist circumference and hypertriglyceridemia (the hypertriglyceridemic-waist phenotype) has been proposed as an inexpensive approach to identify patients with excess intra-abdominal adiposity and associated metabolic abnormalities. We examined the relationship between the hypertriglyceridemic-waist phenotype to the risk of coronary artery disease in apparently healthy individuals. Methods: A total of 21 787 participants aged 45–79 years were followed for a mean of 9.8 (standard deviation 1.7) years. Coronary artery disease developed in 2109 of them during follow-up. The hypertriglyceridemic-waist phenotype was defined as a waist circumference of 90 cm or more and a triglyceride level of 2.0 mmol/L or more in men, and a waist circumference of 85 cm or more and a triglyceride level of 1.5 mmol/L or more in women. Results: Compared with participants who had a waist circumference and triglyceride level below the threshold, those with the hypertriglyceridemic-waist phenotype had higher blood pressure indices, higher levels of apolipoprotein B and C-reactive protein, lower levels of high-density lipoprotein cholesterol and apolipoprotein A-I, and smaller low-density lipoprotein particles. Among men, those with the hypertriglyceridemic-waist phenotype had an unadjusted hazard ratio for future coronary artery disease of 2.40 (95% confidence interval [CI] 2.02–2.87) compared with men who did not have the phenotype. Women with the phenotype had an unadjusted hazard ratio of 3.84 (95% CI 3.20–4.62) compared with women who did not have the phenotype. Interpretation: Among participants from a European cohort representative of a contemporary Western population, the hypertriglyceridemic-waist phenotype was associated with a deteriorated cardiometabolic risk profile and an increased risk for coronary artery disease.

Although many trials have documented the benefits of lowering plasma LDL cholesterol levels for the primary and secondary prevention of cardiovascular disease (CVD), about two thirds of CVD cases cannot be prevented. As CVD morbidity and mortality rates continue to increase in developed and developing societies, despite several improvements in CVD management, this observation suggests that other risk factors beyond LDL cholesterol and other traditional CVD risk factors may yield new insights into the assessment and management of CVD risk. It is now well-recognized that abdominally obese and insulin-resistant individuals have a strong tendency to develop a typical dyslipidemia that is independent of LDL cholesterol levels. This typical dyslipidemia has been called “atherogenic” dyslipidemia in the ATP-III guidelines, which is in fact a misnomer because it implies that other dyslipidemias are not atherogenic. This atherogenic dyslipidemia usually accompanies a high intra-abdominal or visceral adipose tissue (VAT) accumulation and is often associated with elevated plasma levels of triglycerides and apolipoprotein B and with decreased HDL cholesterol and apolipoprotein A-I concentrations. It is also associated with an increased preponderance of small, dense LDL particles which have a stronger tendency to undergo oxidation, even among individuals with plasma LDL cholesterol levels in the normal range. Altogether, these observations suggest that currently available algorithms might not necessarily identify these abdominally obese and dyslipidemic individuals at increased CVD risk. The so-called “hypertriglyceridemic waist” phenotype, on the basis of a simple measurement of waist circumference in combination with plasma triglyceride levels, is a simple tool that can be easily used by general practitioners to identify people carrying atherogenic metabolic abnormalities which put them at increased CVD risk.

Background: The association of metabolic syndrome and risk of CHD is now well established. The association between 'metabolic dyslipidemia' as defined by high triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) levels and the risk of coronary heart disease (CHD) risk is not known. The aim of this study was to investigate the association between metabolic dyslipidemia, and risk of coronary heart disease (CHD) in apparently healthy men and women. Methods: Metabolic dyslipidemia was defined by combination of increased triglyceride (TG) levels (>= 150 mg/dl) and low high-density lipoprotein cholesterol (HDL-C) levels (

Evaluation of: Heslop CL, Frohlich JJ, Hill JS. Myeloperoxidase and C-reactive protein have combined utility for long-term prediction of cardiovascular mortality after coronary angiography. J. Am. Coll. Cardiol. 55(11), 1102–1109 (2010).Identifying people at high risk of cardiovascular events is the cornerstone of cardiovascular disease prevention and a major challenge for healthcare worldwide. Recently, both inflammatory and oxidative markers have been shown to improve cardiovascular risk prediction models in a wide range of patients. Here, we evaluate a recent publication investigating the value of inflammatory and oxidative markers for the prediction of cardiovascular mortality in patients with stable coronary artery disease. This study shows that the use of multiple markers may increase the predictive power of traditional risk models. The findings are discussed in the context of cardiovascular risk prediction in general.

Summary Context Thyroid status affects several aspects of cardiovascular risk profile, including lipid levels and blood pressure. Whether thyroid status affects the risk of coronary heart disease (CHD) and all-cause mortality remains controversial. Design The EPIC-Norfolk prospective population study. Mean follow-up was 10·6 years. Patients Study participants were 11 554 men and women aged 45–79 years, who were living in Norfolk, UK. Measurements Baseline cardiovascular risk factors were recorded and concentrations of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were measured in baseline samples. Regression analyses were performed to assess the association between thyroid hormone levels and cardiovascular risk factors. A proportional hazards model was used to estimate the risk of CHD and all-cause mortality by baseline thyroid status. No information was available on thyroid treatment during follow-up. Results Thyroid abnormalities were common, particularly among women. Thyroid abnormalities were associated with an altered cardiovascular risk profile. Even within the normal range, thyroid hormone levels, TSH more strongly than FT4, were associated with lipid levels and blood pressure among both men and women. We did not observe a significant association between subclinical thyroid abnormalities and risk of CHD or all-cause mortality. Conclusions Despite the association between thyroid hormone levels and cardiovascular risk factors, thyroid status was not statistically significantly associated with the risk of future CHD or all-cause mortality in this large cohort.

Background— Higher lipoprotein-associated phospholipase A 2 (Lp-PLA2) activity is associated with increased risk of coronary heart disease (CHD), making Lp-PLA2 a potential therapeutic target. PLA2G7 variants associated with Lp-PLA2 activity could evaluate whether this relationship is causal. Methods and Results— A meta-analysis including a total of 12 studies (5 prospective, 4 case-control, 1 case-only, and 2 cross-sectional studies; n=26 118) was undertaken to examine the association of the following: (1) Lp-PLA2 activity versus cardiovascular biomarkers and risk factors and CHD events (2 prospective studies; n=4884); (2) PLA2G7 single-nucleotide polymorphisms and Lp-PLA2 activity (3 prospective, 2 case-control, 2 cross-sectional studies; up to n=6094); and (3) PLA2G7 single-nucleotide polymorphisms and angiographic coronary artery disease (2 case-control, 1 case-only study; n=4971 cases) and CHD events (5 prospective, 2 case-control studies; n=5523). Lp-PLA2 activity correlated with several CHD risk markers. Hazard ratios for CHD events for the top versus bottom quartile of Lp-PLA2 activity were 1.61 (95% confidence interval, 1.31 to 1.99) and 1.17 (95% confidence interval, 0.91 to 1.51) after adjustment for baseline traits. Of 7 single-nucleotide polymorphisms, rs1051931 (A379V) showed the strongest association with Lp-PLA2 activity, with VV subjects having 7.2% higher activity than AAs. Genotype was not associated with risk markers, angiographic coronary disease (odds ratio, 1.03; 95% confidence interval, 0.80 to 1.32), or CHD events (odds ratio, 0.98; 95% confidence interval, 0.82 to 1.17). Conclusions— Unlike Lp-PLA2 activity, PLA2G7 variants associated with modest effects on Lp-PLA2 activity were not associated with cardiovascular risk markers, coronary atheroma, or CHD. Larger association studies, identification of single-nucleotide polymorphisms with larger effects, or randomized trials of specific Lp-PLA2 inhibitors are needed to confirm or refute a contributory role for Lp-PLA2 in CHD.

Background: Gradient gel electrophoresis (GGE) and nuclear magnetic resonance (NMR) spectroscopy are both widely accepted methods for measuring LDL and HDL particle size. However, whether or not GGE- or NMR-measured LDL or HDL particle size predicts coronary heart disease (CHD) risk to a similar extent is currently unknown.Methods: We used GGE and NMR to measure LDL and HDL particle size in a nested case-control study of 1025 incident cases of CHD and 1915 controls from the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk study. The study sample included apparently healthy men and women age 45–79 years followed for an average of 6 years.Results: Pearson correlation coefficients showed that the overall agreement between NMR and GGE was better for the measurement of HDL size (r = 0.78) than for LDL size (r = 0.47). The odds ratio for future CHD among participants in the bottom tertile of LDL size (smallest LDL particles) was 1.35 (95% CI, 1.12–1.63) for GGE and 1.74 (1.41–2.15) for NMR. For HDL size, these respective odds ratios were 1.41 (1.16–1.72) and 1.85 (1.47–2.32). After adjustment for potential confounders, the relationship between small LDL or HDL particles and CHD was no longer significant, irrespective of the method.Conclusions: In this prospective population study, we found that the relationships between NMR-measured LDL and HDL sizes and CHD risk were slightly higher than those obtained with GGE.

Background— Prolactin is increasingly recognized to play a stimulatory role in the inflammatory response. Because inflammation is considered of crucial importance in the development of atherosclerosis, we aimed to evaluate whether prolactin levels are associated with the occurrence of coronary artery disease (CAD). Methods and Results— We performed a nested case-control study in the prospective EPIC-Norfolk cohort. Cases were apparently healthy men and women, aged 45 to 79 years, who developed fatal or nonfatal CAD (n=882). Controls remained free of CAD (n=1490). Overall, systemic prolactin levels did not differ between cases and controls, and people in the highest prolactin tertile did not have a significantly increased risk of developing future CAD (in men, odds ratio, 1.21; 95% CI, 0.92 to 1.61; in women, odds ratio, 1.12; 95% CI, 0.76 to 1.64). However, in a separate immunohistochemical study, the presence of prolactin receptors could be demonstrated in postmortem human coronary artery plaques (preliminary data). Conclusions— Elevated systemic prolactin levels do not predict CAD in the general population. However, prolactin receptors were found in human coronary artery plaques. This observation may indicate a role of prolactin within atherosclerotic plaques. More studies are needed to define the possible role of prolactin in atherosclerotic plaque development.

Objectives This study sought to assess whether oxidation-specific biomarkers are associated with an increased risk of coronary artery disease (CAD) events. Background The relationship of a panel of oxidative biomarkers and lipoprotein(a) [Lp(a)] to CAD risk is not fully determined. Methods A prospective case-control study nested in the EPIC (European Prospective Investigation of Cancer)-Norfolk cohort of 45- to 79-year-old apparently healthy men and women followed for similar to 6 years was designed. Cases consisted of participants in whom fatal or nonfatal CAD developed, matched by sex, age, and enrollment time with controls without CAD. Baseline levels of oxidized phospholipids on apolipoprotein B-100 particles and Lp(a) were measured in 763 cases and 1,397 controls. Their relationship to secretory phospholipase A(2) type IIA mass and activity, myeloperoxidase mass, and lipoprotein-associated phospholipase A(2) activity and association with CAD events were determined. Results After adjusting for age, smoking, diabetes, low-and high-density lipoprotein cholesterol, and systolic blood pressure, the highest tertiles of oxidized phospholipids on apolipoprotein B-100 particles and Lp(a) were associated with a significantly higher risk of CAD events (odds ratios: 1.67 and 1.64, respectively; p

Objectives : Low levels of high-density lipoprotein cholesterol (HDL-C) are a risk factor for coronary artery disease (CAD) and possibly for deep venous thrombosis (DVT). Endothelial lipase is involved in HDL-C metabolism. Common variants in the endothelial lipase gene ( LIPG ) have been reported to be associated with HDL-C levels and atherothrombosis, but these findings were not consistent. We determined whether five tagging single nucleotide polymorphisms (SNP) in LIPG were associated with lipid parameters, the risk of CAD and the risk of DVT. Methods : We used the prospective case–control study nested in the EPIC-Norfolk cohort (1138 CAD cases, 2237 matched controls) for the initial association study and, subsequently, the ACT study (185 patients with documented DVT, 586 patients in which DVT was ruled out) to replicate our findings regarding DVT risk. Results : In EPIC-Norfolk, we found that the minor allele of one SNP, rs2000813 (p.T111I), was associated with moderately higher HDL-C and apolipoprotein A-I levels, higher HDL particle number and larger HDL size. No variants were associated with CAD risk, but three variants were associated with DVT risk (odds ratios 0.60 [95%CI 0.43–0.84], 2.04 [95%CI 1.40–2.98] and 1.67 [95%CI 1.18–2.38] per minor allele for rs2000813, rs6507931 and rs2097055 respectively, p LIPG SNPs and DVT risk could not be replicated in the ACT study. Conclusions : Our data support a modest association between the LIPG rs2000813 variant and parameters of HDL metabolism, but no association between common genetic variants in LIPG and CAD or DVT risk.

Paraoxonase-1 (PON1) is an antioxidant enzyme, that resides on high-density lipoprotein (HDL). PON1-activity, is heavily influenced by the PON1-Q192R polymorphism. PON1 is considered to protect against atherosclerosis, but it is unclear whether this relation is independent of its carrier, HDL. In order to evaluate the atheroprotective potential of PON1, we assessed the relationships among PON1-genotype, PON1-activity and risk of future coronary artery disease (CAD), in a large prospective case-control study. Methodology/Principal Findings: Cases (n = 1138) were apparently healthy men and women aged 45-79 years who developed fatal or nonfatal CAD during a mean follow-up of 6 years. Controls (n = 2237) were matched by age, sex and enrollment time. PON1-activity was similar in cases and controls (60.7 +/- 645.3 versus 62.6 +/- 645.8 U/L, p = 0.3) and correlated with HDL-cholesterol levels (r = 0.16, p < 0.0001). The PON1-Q192R polymorphism had a profound impact on PON1-activity, but did not predict CAD risk (Odds Ratio [OR] per R allele 0.98[0.84-1.15], p = 0.8). Using conditional logistic regression, quartiles of PON1-activity showed a modest inverse relation with CAD risk (OR for the highest versus the lowest quartile 0.77[0.63-0.95], p = 0.01; p-trend = 0.06). PON1-activity adjusted for Q192R polymorphism correlated better with HDL-cholesterol (r = 0.26, p < 0.0001) and more linearly predicted CAD risk (0.79[0.64-0.98], p = 0.03; p-trend = 0.008). However, these relationships were abolished after adjustment for HDL (particles-cholesterol-size) and apolipoprotein A-l (0.94[0.74-1.18], p-trend = 0.3). Conclusions/Significance: This study, shows that PON1-activity inversely relates to CAD risk, but not independent of HDL, due to its close association with the HDL-particle. These data strongly suggest that a low PON1-activity is not a causal factor in atherogenesis

This study was designed to test the hypothesis that at any low-density lipoprotein cholesterol (LDL-C) level, other lipid parameters such as non-high-density lipoprotein cholesterol (HDL-C) levels, triglyceride (TG) levels, and the total cholesterol (TC)/HDL-C are still associated with an increased coronary heart disease (CHD) risk.Although LDL-C is considered to be the primary target of lipid-lowering therapy, other parameters of the lipoprotein-lipid profile may more closely associated with CHD risk.In the EPIC (European Prospective Investigation Into Cancer and Nutrition)-Norfolk prospective population study, 21,448 participants without diabetes or CHD between age 45 and 79 years were followed for 11.0 years. A total of 2,086 participants developed CHD during follow-up.Among individuals with low LDL-C levels (100 mg/dl), after adjustment for age, sex, smoking, systolic blood pressure, waist circumference, physical activity, and hormone replacement therapy (in women), those with non-HDL-C130 mg/dl had a hazard ratio (HR) for future CHD of 1.84 (95% confidence interval [CI]: 1.12 to 3.04) when compared with those with non-HDL-C levels130 mg/dl. In a similar model, individuals with TG levels150 mg/dl had an HR of 1.63 (95% CI: 1.02 to 2.59) when compared with those with TG levels150 mg/dl, and individuals with a TC/HDL-C ratio5 had an HR of 2.19 (95% CI: 1.22 to 3.93) when compared with those with a TC/HDL-C ratio5.In this prospective study, independently of their plasma LDL-C levels, participants with high non-HDL-C levels, high TG levels, or with an elevated TC/HDL-C ratio were at increased CHD risk. CHD risk assessment algorithms as well as lipid targets of lipid-lowering trials may also need to consider other easily available parameters such as non-HDL-C.

Objective— The purpose of this study was to examine the association between serum levels of osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) and future coronary artery disease (CAD) in apparently healthy individuals. The identification of OPG as a novel cardiovascular risk marker suggests an association between mediators of bone homeostasis and cardiovascular disease. Methods and Results— Serum levels of OPG and RANKL were analyzed in a prospective case–control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) study, a cohort study of 25 663 men and women, where 951 apparently healthy individuals who developed a coronary event during 6 years’ follow-up were matched by sex and age with 1705 healthy controls. Baseline OPG, but not RANKL, was higher in cases than in controls, and OPG was higher in women than in men. Both men and women in the highest OPG quartile had a higher risk for future CAD. These associations were independent of established cardiovascular risk factors, and when using OPG as a continuous variable, also after adjustment for CRP. In contrast, RANKL showed no association with coronary events. Conclusion— OPG is associated with the risk of future CAD in apparently healthy men and women, independent of established cardiovascular risk factors.

Aims The aim of this study was to determine the contribution of physical activity and abdominal obesity to the variation in inflammatory biomarkers and incident coronary heart disease (CHD) in a European population. Methods and results In a prospective case–control study nested in the European Prospective Investigation into Cancer and Nutrition-Norfolk cohort, we examined the associations between circulating levels or activity of C-reactive protein, myeloperoxidase (MPO), secretory phospholipase A2 (sPLA2), lipoprotein-associated phospholipase A2 (Lp-PLA2), fibrinogen, adiponectin, waist circumference, physical activity, and CHD risk over a 10-year period among healthy men and women (45–79 years of age). A total of 1002 cases who developed fatal or non-fatal CHD were matched to 1859 controls on the basis of age, sex, and enrolment period. Circulating levels of C-reactive protein, sPLA2 (women only), fibrinogen, and adiponectin were linearly associated with increasing waist circumference and decreasing physical activity levels. After adjusting for waist circumference, physical activity, smoking, diabetes, systolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol levels, and further adjusted for hormone replacement therapy in women, C-reactive protein, MPO (men only), sPLA2, fibrinogen, but not Lp-PLA2 and adiponectin were associated with an increased CHD risk. Conclusion Inactive participants with an elevated waist circumference were characterized by deteriorated levels of inflammatory markers. However, several inflammatory markers were associated with an increased CHD risk, independent of underlying CHD risk factors such as waist circumference and physical activity levels.

Background: High-density lipoprotein (HDL) cholesterol levels are inversely related to risk for coronary artery disease (CAD). Because HDL particles are heterogeneous in size and composition, they may be differentially associated with other cardiovascular risk factors and with cardiovascular risk. Objective: To study the independent relationships of HDL size and particle concentration to risk for future CAD. Design: Nested case-control study within the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk cohort; baseline survey between 1993 and 1997, follow-up until November 2003. Setting: Norfolk, United Kingdom. Participants: Case patients were 822 apparently healthy men and women who developed CAD during follow-up. Control participants were 1401 participants who remained without CAD and were matched to case patients by sex, age, and enrollment time. Measurements: First CAD event leading to either hospitalization or death. Results: Nuclear magnetic resonance spectroscopy-measured HDL particle concentration (mean, 33.9 mu mol/L [SD, 5] vs. 32.9 mu mol/L [SD, 6]; P

CONTEXT: Recent studies reported that retinol-binding protein 4 (RBP4) has a causal role in insulin resistance and suggested that its circulating levels may predict cardiovascular disease. However, the latter assumption has not yet been tested. OBJECTIVE: We assessed the value of RBP4 measurement in the prediction of incident coronary artery disease (CAD). DESIGN: We conducted a nested case-control study of incident CAD (n = 1036 cases vs. n = 1889 controls) selected from among 25,336 participants of the EPIC-Norfolk study. SETTING: Healthy men and women, aged between 45 and 79 yr, were recruited from age-sex registers of general practices in Norfolk. PATIENTS AND OTHER PARTICIPANTS: Participants completed a baseline questionnaire survey between 1993 and 1997, attended a clinic visit, and were followed for an average of 6 yr. Cases (n = 1036) were participants who developed CAD during the follow-up. Controls (n = 1889) matched by age, sex, and enrollment time remained free of any CAD during follow-up. MAIN OUTCOMES MEASURE: Risk of incident fatal or nonfatal CAD according to RBP4 quartiles was assessed. RESULTS: RBP4 levels were higher in cases than in controls. RBP4 levels correlated weakly with body mass index, waist-to-hip ratio, systolic and diastolic blood pressure, and total and low-density lipoprotein-cholesterol and were inversely associated with C-reactive protein concentrations. The strongest correlation was found with triglycerides. The risk of incident CAD was associated with increasing quartiles of RBP4 levels (P = 0.03). However, adjustment for cardiovascular risk factors abolished this association. CONCLUSIONS: Measurement of serum RBP4 does not provide added value for predicting CAD risk beyond traditional risk factors

Objective: To evaluate the association between HDL particle size measured by gradient gel electrophoresis and risk of incident coronary heart disease (CHD) in apparently healthy men and women. Methods: We performed a prospective case-control study nested in the EPIC-Norfolk cohort. Cases were apparently healthy men and women aged 45-79 years who developed fatal or nonfatal CHD (n = 1035). They were matched to 1920 controls who remained free of CHD over the follow-up period of 6 years. Results: Participants with the smallest HDL particles had the most unfavourable cardiometabolic risk profile whereas those with the largest HDL particles had the most favourable risk profile. Plasma HDL cholesterol levels were found to be the best correlate of HDL particle size (r = 0.58 and r = 0.62, respectively, for men and women, p

Objective: To investigate how C-reactive protein (CRP) and major depressive disorder (MDD) relate to each other and to incident ischemic heart disease (IHD). Studies have shown that both depression and raised CRP concentration predict IHD and that elevated CRP is linked with increased risk of depression. Methods: A prospective case-control study of healthy men and women, aged 45 to 79 years, was undertaken within the United Kingdom European Prospective Investigation into Cancer (EPIC)-Norfolk study. CRP concentration was measured for 726 (fatal or nonfatal) IHD cases and 1688 matched controls who completed a baseline MDD self-assessment, defined by restricted Diagnostic and Statistical Manual of Mental Disorders, 4th Edition diagnostic criteria. Results: Past-year MDD was associated with increased CRP concentration levels (4.31 mg/L for participants who reported episodes of MDD in the past year versus 3.65 mg/L for those who did not; p =.003), and the odds ratio for incident IHD associated with higher CRP concentration was 2.02 (comparing the top versus bottom quartile of CRP; 95% Confidence Interval (CI) = 1.52-2.68), adjusted for cigarette smoking, diabetes, systolic blood pressure, body mass index, and cholesterol. The association between past-year MDD and IHD was independent of CRP (odds ratio = 1.55; 95% Cl = 1.01-2.37, with adjustments as above, and additionally for CRP). Conclusions: Evidence from this study is supportive of an association between MDD and CRP although it suggests that CRP does not account for the association between MDD and future IHD

There is a continuous relationship between glycated hemoglobin (HbA(1c)) and coronary heart disease (CHD) risk, even below diagnostic thresholds for diabetes mellitus.To evaluate the Framingham risk score in a UK population-based prospective cohort (European Prospective Investigation of Cancer [EPIC]-Norfolk) and to assess whether adding HbA(1c) improves the prediction of CHD. Participants aged 40 to 79 years were recruited from UK general practices, attended a health check, and were followed up for CHD events and death. The Framingham risk score was computed for 10,295 individuals with data on age, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, diabetes mellitus, and smoking status. We developed a Cox proportional hazards regression model with the original Framingham covariates and then added HbA(1c) to determine whether this improved the prediction of CHD. Model discrimination was compared by using area under the receiver operating characteristic curves (AUROCs), and the correctness of reclassification was determined by calculating the net reclassification improvement and the integrated discrimination improvement. The main outcome measures were CHD-related hospital admission and death.A total of 430 men and 250 women developed CHD during 8.5 years of follow-up. The AUROC for the original Framingham risk score was 0.71. Using the Framingham variables with coefficients fitted from the EPIC-Norfolk data, the AUROC was 0.72 for men and 0.80 for women, compared with 0.73 and 0.80, respectively, in a score including HbA(1c). This difference was significant for men only (P = .005). The net reclassification improvement was 3.4% (P = .06) in men and -2.2% (P = .27) in women.The Framingham risk score predicts CHD in this cohort. The addition of HbA(1c) made a small but statistically significant improvement to discrimination in men but not in women, without significant improvement in reclassification of risk category.

Background— Low-density lipoprotein (LDL) cholesterol is the principal target of lipid-lowering therapy, but recent evidence has suggested more appropriate targets. We compared the relationships of on-treatment levels of LDL cholesterol, non–high-density lipoprotein (HDL) cholesterol, and apolipoprotein B, as well as ratios of total/HDL cholesterol, LDL/HDL cholesterol, and apolipoprotein B/A-I, with the occurrence of cardiovascular events in patients receiving statin therapy. Methods and Results— A post hoc analysis was performed that combined data from 2 prospective, randomized clinical trials in which 10 001 (“Treating to New Targets”) and 8888 (“Incremental Decrease in End Points through Aggressive Lipid Lowering”) patients with established coronary heart disease were assigned to usual-dose or high-dose statin treatment. In models with LDL cholesterol, non-HDL cholesterol and apolipoprotein B were positively associated with cardiovascular outcome, whereas a positive relationship with LDL cholesterol was lost. In a model that contained non-HDL cholesterol and apolipoprotein B, neither was significant owing to collinearity. Total/HDL cholesterol ratio and the apolipoprotein B/A-I ratio in particular were each more closely associated with outcome than any of the individual proatherogenic lipoprotein parameters. Conclusions— In patients receiving statin therapy, on-treatment levels of non-HDL cholesterol and apolipoprotein B were more closely associated with cardiovascular outcome than levels of LDL cholesterol. Inclusion of measurements of the antiatherogenic lipoprotein fraction further strengthened the relationships. These data support the use of non-HDL cholesterol or apolipoprotein B as novel treatment targets for statin therapy. Given the absence of interventions that have been proven to consistently reduce cardiovascular disease risk through raising plasma levels of HDL cholesterol or apolipoprotein A-I, it seems premature to consider the ratio variables as clinically useful.

Background— Angiopoietin-like 4 is a dual-function protein: an inhibitor of LPL, influencing plasma triglycerides (TGs), with angiogenic properties. We examined the association of common ANGPTL4 variants with CHD traits and risk in 5 studies (13 527 individuals). Methods and Results— The effects on plasma lipids of 6 tagging SNPs and the recently identified E40K were examined in a study of 2772 men. Only T266M (rs1044250, MAF=30%) and E40K (MAF=2%) were significantly associated with TG-lowering (−10.4%, P P P =0.2). Combining data from 5 studies confirmed the TG-lowering effect of K40+ (weighted mean difference: −0.12 [95% CI −0.18, −0.05] mmol/L TG P =0.0001). Surprisingly, in the 3 prospective studies, the combined OR for CHD was 1.48 (1.11 to 1.96, P =0.007), independent of TG. In individuals with a paternal history of MI (n=332) T266M, but not E40K, showed effects on postprandial AUC TG and glucose ( P =0.009 and P =0.017, respectively) compared to controls (n=370). Conclusion— Although associated with an atheroprotective lipid profile, E40K was associated with increased CHD risk, suggesting Angptl4 influences parameters beyond lipid levels. T266M showed effects only under conditions of postprandial stress. The functionality of these potential “loss-of-function” variants needs validation.

AIMS: To evaluate the association of low-density lipoprotein cholesterol (LDL-C) levels in small and large LDL particles with risk of incident coronary heart disease (CHD). METHODS AND RESULTS: We performed a prospective case-control study nested in the EPIC-Norfolk cohort. Cases were apparently healthy men and women aged 45-79 years who developed fatal or non-fatal CHD (n = 1035), and who were matched by age, gender, and enrollment time to 1920 controls who remained free of CHD. Electrophoretic characteristics of LDL particles were measured using 2-16% polyacrylamide gradient gel electrophoresis. Concentrations of LDL-C(

This study was designed to assess the relationship of high-density-lipoprotein cholesterol (HDL-C), HDL particle size, and apolipoprotein A-I (apoA-I) with the occurrence of coronary artery disease (CAD), with a focus on the effect of very high values of these parameters.High plasma levels of HDL-C and apoA-I are inversely related to the risk of CAD. However, recent data suggest that this relationship does not hold true for very high HDL-C levels, particularly when a preponderance of large HDL particles is observed.We conducted a post-hoc analysis of 2 prospective studies: the IDEAL (Incremental Decrease in End Points through Aggressive Lipid Lowering; n = 8,888) trial comparing the efficacy of high-dose to usual-dose statin treatment for the secondary prevention of cardiovascular events, and the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk case-control study, including apparently healthy individuals who did (cases, n = 858) or did not (control patients, n = 1,491) develop CAD during follow-up. In IDEAL, only HDL-C and apoA-I were available; in EPIC-Norfolk, nuclear magnetic resonance spectroscopy-determined HDL particle sizes were also available.In the IDEAL study, higher HDL-C proved a significant major cardiac event risk factor following adjustment for age, gender, smoking, apoA-I, and apoB. A similar association was observed for HDL particle size in EPIC-Norfolk. Increased risk estimates were particularly present in the high ends of the distributions. In contrast, apoA-I remained negatively associated across the major part of its distribution in both studies.When apoA-I and apoB are kept constant, HDL-C and HDL particle size may confer risk at very high values. This does not hold true for very high levels of apoA-I at fixed levels of HDL-C and apoB. These findings may have important consequences for assessment and treatment of CAD risk.

An elevated apolipoprotein B-apolipoprotein A-I (apo B-apo A-I) ratio is a risk factor for future coronary artery disease (CAD). It is not known whether this ratio is better than traditional lipid values for risk assessment and prediction and whether it adds predictive value to the Framingham risk score.To evaluate whether the apo B-apo A-I ratio is associated with future CAD events independent of traditional lipid measurements and the Framingham risk score and to evaluate the ability of this ratio to predict occurrence of future CAD.Prospective, nested case-control study.Norfolk, United Kingdom.Apparently healthy men and women (45 to 79 years of age) in the European Prospective Investigation into Cancer and Nutrition-Norfolk. Cases (n = 869) were persons who developed fatal or nonfatal CAD. Controls (n = 1511) were persons without CAD who were matched for age, sex, and enrollment period.Total cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, apolipoprotein, and C-reactive protein levels were measured directly. Low-density lipoprotein (LDL) cholesterol values were calculated by using the Friedewald formula.The apo B-apo A-I ratio was associated with future CAD events, independent of traditional lipid values (adjusted odds ratio, 1.85 [95% CI, 1.15 to 2.98]), including the total cholesterol-HDL cholesterol ratio, and independent of the Framingham risk score (adjusted odds ratio, 1.77 [CI, 1.31 to 2.39]). However, it did no better than lipid values at discriminating between CAD cases and controls (area under the receiver-operating characteristic curve, 0.670 for total cholesterol-HDL cholesterol ratio vs. 0.673 for apo B-apo A-I ratio [P = 0.38]) and added little to the predictive value of the Framingham risk score (area under the receiver-operating characteristic curve, 0.594 for Framingham risk score alone vs. 0.613 for Framingham risk score plus apo B-apo A-I ratio [P0.001]). In addition, it incorrectly classified 41.1% of cases and 50.4% of controls.No participant was taking lipid-lowering medication, and diabetes was uncommon.The apo B-apo A-I ratio is independently associated with, but adds little to, existing measures for CAD risk assessment and discrimination in the general population. Other characteristics of the test, such as the ability to perform it on nonfasting samples, may still make it useful in some settings.

We evaluated whether serum myeloperoxidase (MPO) levels are associated with the risk of future development of coronary artery disease (CAD) in apparently healthy individuals.An enzyme of the innate immune system, MPO exhibits a wide array of proatherogenic effects. These include induction of oxidative damage to low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol and promotion of plaque vulnerability. Recent studies revealed that MPO independently predicts adverse outcomes in patients with chest pain or suspected acute coronary syndrome.Myeloperoxidase was measured in baseline samples of a case-control study nested in the prospective EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk population study. Case subjects (n = 1,138) were apparently healthy men and women who developed CAD during 8-year follow-up. Control subjects (n = 2,237), matched for age, gender, and enrollment time, remained free of CAD.The MPO levels were significantly higher in case subjects than in control subjects and correlated with C-reactive protein (CRP) (rho = 0.25; p0.001) and white blood cell count (rho = 0.33; p0.001). Risk of future CAD increased in consecutive quartiles of MPO concentration, with an odds ratio (OR) of 1.49 in the top versus bottom quartile (95% confidence interval [CI] 1.20 to 1.84; p0.001). After adjustment for traditional risk factors, the OR in the top quartile remained significant at 1.36 (95% CI 1.07 to 1.73). Elevated MPO levels (728 pmol/l) similarly predicted increased risk of future CAD among participants with either LDL-cholesterol130 mg/dl, HDL-cholesterol50 mg/dl, or CRP2.0 mg/l (OR 1.52 [95% CI 1.21 to 1.91], 1.59 [95% CI 1.24 to 2.05], and 1.42 [95% CI 1.14 to 1.77)], respectively).Elevated MPO levels predict future risk of CAD in apparently healthy individuals. This study suggests that inflammatory activation precedes the onset of overt CAD by many years.

High plasma concentrations of ascorbic acid, a marker of fruit and vegetable intake, are associated with low risk of coronary artery disease. Whether this relationship is explained by a reduction in systemic inflammation is unclear. We investigated the relationship between ascorbic acid plasma concentration and coronary artery disease risk, and in addition whether this relationship depended on classical risk factors and C-reactive protein (CRP) concentration. We used a prospective nested case-control design. The study consisted of 979 cases and 1794 controls (1767 men and 1006 women). Increasing ascorbic acid quartiles were associated with lower age, BMI, systolic and diastolic blood pressure, and CRP concentration, but with higher HDL-cholesterol concentration. No associations existed between ascorbic acid concentration and total cholesterol concentration or LDL-cholesterol concentration. When data from men and women were pooled, the risk estimates decreased with increasing ascorbic acid quartiles such that people in the highest ascorbic acid quartile had an odds ratio for future coronary artery disease of 0.67 (95 % CI 0.52, 0.87) compared with those in the lowest quartile (P for linearity=0.001). This relationship was independent of sex, age, diabetes, smoking, BMI, LDL-cholesterol, HDL-cholesterol, systolic blood pressure and CRP level. These data suggest that the risk reduction associated with higher ascorbic acid plasma concentrations, a marker of fruit and vegetable intake, is independent of classical risk factors and also independent of CRP concentration.

Objective— To determine the association between serum levels of mannose-binding lectin (MBL) and the risk of future coronary artery disease (CAD) in apparently healthy men and women. Methods and Results— We performed a prospective case-control study among apparently healthy men and women nested in the EPIC-Norfolk cohort. Baseline concentrations of MBL were measured in serum samples of 946 patients who experienced a myocardial infarction or died of CAD during follow-up, and 1799 matched controls who remained free of CAD. Among men, median MBL levels were 1.63 ng/mL (interquartile range [IQR]: 0.59 to 3.80) in cases and 1.20 ng/mL (IQR: 0.48 to 3.37) in controls. Among women, median MBL levels were 1.02 ng/mL (IQR: 0.43 to 2.95) in cases and 1.01 ng/mL (IQR: 0.43 to 2.94) in controls. After adjustment, the odds ratio in men for future CAD was 1.59 (95% confidence interval [CI]: 1.09 to 2.32; P for linearity=0.01) for those in the highest quartile compared with those in the lowest quartile. In women no such relation was observed. Conclusions— Elevated levels of MBL are associated with an increased risk of future CAD in apparently healthy men but not in women. The sex difference merits further exploration.

Raising high-density lipoprotein cholesterol (HDL-C) is a promising strategy in the struggle to prevent cardiovascular disease, and cholesteryl ester transfer protein (CETP) inhibitors have been developed to accomplish this. The first results are encouraging, and, in fact, in rabbits, inhibition of CETP reduces atherosclerosis. Because human data regarding the reduction of atheroma burden require more time, the biochemical mechanisms underlying the putative atheroprotection of CETP inhibitors are currently dissected, and several pathways have emerged. First, CETP inhibition increases HDL-C and reduces low-density lipoprotein cholesterol (LDL-C) levels consistent with CETP lipid transfer activity and its role in reverse cholesterol transport (RCT). This coincides with putative beneficial increases in both HDL and LDL size. However, many aspects regarding the impact of CETP inhibition on the RCT pathway remain elusive, in particular whether the first step concerning cholesterol efflux from peripheral tissues to HDL is influenced. Moreover, the relevance of scavenger receptor BI and consequently the central role of HDL in human RCT is still unclear. Second, CETP inhibition was shown recently to increase antioxidant enzymes associated with HDL, in turn associated with decreased oxidation of LDL. Atheroprotection in man is currently anticipated based on the improvement of these biochemical parameters known to influence atherosclerosis, but final confirmation regarding the impact of CETP inhibition on cardiovascular outcome will have to come from trials evaluating clinical end points.

The objective of this study was to determine the extent to which common genetic variants can explain the variation of high-density lipoprotein cholesterol (HDL-C) plasma levels in familial hypercholesterolemia (FH). FH is characterized by elevated low-density lipoprotein cholesterol levels and premature cardiovascular disease (CVD). Although low HDL-C levels have been shown to affect the severity of the clinical phenotype, little is known about the factors that determine HDL-C levels in these patients. A cohort of 1002 heterozygous FH patients was genotyped for polymorphisms in the genes encoding for ATP-binding cassette transporter A1, apolipoprotein (apo) AIV, apoCIII, apoE, cholesteryl transfer ester protein, hepatic lipase, lipoprotein lipase, and two paraoxonases. Multiple linear regression showed that, together, these polymorphisms explain only 3.9% of the variation of HDL-C plasma levels. When significant two-way interactions between the polymorphisms were also taken into account, the explained variation rose to 12.5%. In a regression model that also incorporated sex, smoking, alcohol use, body mass index, and concomitant beta-blocker use as covariates, the explained variation of HDL-C plasma levels even increased to 32.5%. This study provides direct evidence that multiple, modestly penetrant, but highly prevalent, polymorphisms can explain a substantial part of the variation of HDL-C plasma levels in a representative large cohort of heterozygous FH patients.

Background— Low plasma levels of cholesteryl ester transfer protein (CETP) are associated with elevated levels of HDL cholesterol (HDL-C), but it remains unclear whether this translates into a concomitant reduction in the risk of coronary artery disease (CAD). Evidence exists that the effect of CETP depends on metabolic context, in particular on triglyceride levels. Methods and Results— A nested case-control study was performed in the prospective EPIC-Norfolk cohort study. Cases were apparently healthy men and women aged 45 to 79 years who developed fatal or nonfatal CAD during follow-up. Control subjects were matched by age, sex, and enrollment time. CETP levels were not significantly different between cases and controls (4.0±2.2 versus 3.8±2.1 mg/L, P =0.07). CETP levels were significantly related to plasma levels of total cholesterol, LDL cholesterol, and HDL-C. The risk of CAD increased with increasing CETP quintiles ( P for linearity=0.02), such that subjects in the highest quintile had an adjusted OR of 1.43 (95% CI 1.03 to 1.99, P =0.03) versus those in the lowest. Among individuals with triglyceride levels below the median (1.7 mmol/L), no relationship between CETP levels and CAD risk was observed ( P for linearity=0.5), but this relationship was strong among those with high triglyceride levels ( P for linearity=0.02), such that those in the highest CETP quintile had an OR of 1.87 (95% CI 1.06 to 3.30, P =0.02). Conclusions— Elevated CETP levels are associated with an increasing risk of future CAD in apparently healthy individuals, but only in those with high triglyceride levels.

PURPOSE: To determine whether plasma levels of macrophage migration inhibitory factor, a proinflammatory cytokine involved in atherogenesis, are predictive of myocardial infarction or death from coronary artery disease. METHODS: We performed a prospective case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort. We selected men and women who did not report a history of myocardial infarction or stroke at baseline. Baseline concentrations of macrophage migration inhibitory factor were measured among 777 patients who had a myocardial infarction or died of coronary artery disease during follow-up, and 1554 matched controls who remained free of coronary artery disease. RESULTS: Baseline macrophage migration inhibitory factor concentrations were higher in cases than controls (median, 107.4 mug/L vs. 90.7 mug/L, P = 0.001). The risk of myocardial infarction or death from coronary artery disease increased with increasing quartiles of macrophage migration inhibitory factor (P for linearity

Background: The PlA1A2 polymorphism of glycoprotein IIIa (GPIIIa), which affects postoccupancy signaling by the platelet fibrinogen receptor IIbIIIa, has been investigated as a potential genetic risk factor for cardiovascular events in numerous studies, without consistent results. We investigated whether the effect of this genetic variant of the platelet fibrinogen receptor on the risk of cardiovascular events is affected by fibrinogen plasma levels. Methods: The GPIIIa PlA1A2 polymorphism and fibrinogen levels were determined in 455 men with angiographically documented coronary atherosclerosis. Results: Neither carriership of the rare PlA2 allele nor fibrinogen plasma levels affected the time to cardiovascular event, as assessed in a proportional hazards model. However, there was a significant interaction between PlA2 carriership and fibrinogen plasma levels (P = .002). Carriership of the variant PlA2 allele significantly affected event-free survival only in individuals within the highest fibrinogen quartile (hazard ratio, 2.7; 95% CI, 1.1 to 7.1; P = .03). Conclusions: We observed a statistically significant interaction between a genetic variant of the platelet fibrinogen receptor and fibrinogen levels in determining the risk of cardiovascular events. This interaction may account for the inconsistent results of genetic association studies investigating this genotype as a genetic risk factor in thrombotic cardiovascular events. Chemicals/CAS: fibrinogen, 9001-32-5; Fibrinogen, 9001-32-5; Integrin beta3; Platelet Glycoprotein GPIIb-IIIa Complex; Pravastatin, 81093-37-0; Receptors, Fibrinogen

Background— Atherosclerosis is increasingly considered to be a chronic inflammatory process. We examined whether genetic variants of the toll-like receptor 4 (TLR4), which are correlated with impaired innate immunity and with progression of carotid atherosclerosis, are also associated with coronary atherosclerosis and predict the risk of cardiovascular events. Methods and Results— Two polymorphisms of the TLR4 gene (Asp299Gly and Thr399Ile) were determined in 655 men with angiographically documented coronary atherosclerosis. All patients participated in a prospective cholesterol-lowering trial evaluating the effect on coronary artery disease and were randomly assigned to either pravastatin or placebo for 2 years. There were no significant differences between genetically defined subgroups with respect to baseline risk factors, treatment, or in-trial changes of lipid, lipoprotein, or angiographic measurements. Genotype was not associated with progression of atherosclerosis. In the pravastatin group, 299Gly carriers had a lower risk of cardiovascular events during follow-up than noncarriers (2.0% versus 11.5%, P =0.045). Among noncarriers, pravastatin reduced the risk of cardiovascular events from 18.1% to 11.5% ( P =0.03), whereas among 299Gly carriers this risk was strikingly reduced from 29.6% to 2.0% ( P =0.0002, P =0.025 for interaction). Conclusions— Among symptomatic men with documented coronary artery disease, the TLR4 Asp299Gly polymorphism was associated with the risk of cardiovascular events. This variant also modified the efficacy of pravastatin in preventing cardiovascular events, such that carriers of the variant allele had significantly more benefit from pravastatin treatment.

Since the identification of cholesteryl ester trans- fer protein (CETP), its role in the modulation of HDL levels and cardiovascular disease has been debated. With the early detection of genetic variants followed by the finding of fami- lies deficient in CETP, genetic studies have played a large role in the attempts to understand the association of CETP with lipids and disease; however, results of these studies have often led to disparate conclusions. With the availability of a greater variety of genetic polymorphisms and larger studies in which disease has been examined, it is now possible to compare the breadth of CETP genetic studies and draw bet- ter conclusions. The most broadly studied polymorphism is TaqIB for which over 10,000 individuals have been geno- typed and had HDL levels determined. When these studies are subjected to a meta-analysis, the B2B2 homozygotes are found to have higher HDL levels than B1B1 homozygotes (0.12 mmol/l, 95% CI � 0.11-0.13, P � 0.0001). A similar analysis of the I405V polymorphism yields 0.05 mmol/l higher HDL levels in 405VV homozygotes than in 405II ho- mozygotes (95% CI � 0.03-0.07, P � 0.0001). The impli- cations of these studies for cardiovascular disease will be ad- dressed. —Boekholdt, S. M., and J. F. Thompson. Natural genetic variation as a tool in understanding the role of CETP in lipid levels and disease. J. Lipid Res. 2003. 44: 1080-1093.

Objective— Recently, polymorphisms in thrombospondin (THBS) genes coding for THBS-1 (N700S), THBS-2 (T>G substitution in 3′-untranslated region), and THBS-4 (A387P) genes were proposed to modulate the risk of premature coronary artery disease (CAD) or myocardial infarction (MI). It was our objective to verify this hypothesis in an independent cohort. Methods and Results— We performed a case-control study among patients (n=503) referred to our institution for symptomatic CAD that occurred before the age of 50 years and a group of age- and sex-matched population-based controls free of CAD (n=1071). The THBS-1 variant allele was not associated with an altered risk of premature CAD or MI. Homozygosity for the THBS-2 variant allele and the THBS-4 variant (387P) allele was significantly associated with a reduced risk of premature MI compared with wild-type individuals (OR=0.44, 0.24 to 0.84 and OR=0.43, 0.22 to 0.85, respectively). The latter observation is in contrast with a previous report, although confidence intervals overlap. Conclusions— We conclude that a relationship between the THBS-1 N700S polymorphism and premature CAD is unlikely. For the THBS-4 A387P polymorphism, additional studies are required to elucidate its role in premature CAD. Finally, we conclude that the THBS-2 polymorphism is associated with a reduced risk of premature MI.

Today, a person's genetic background is considered in every aspect of clinical medicine, ranging from susceptibility to diseases, pathogenesis, and clinical outcome to diversity in responses to dru...

Background — It is pathophysiologically conceivable that genetic variations in coagulation and fibrinolytic proteins are associated with the risk of myocardial infarction. Methods and Results — We performed a literature search to identify published case-control studies correlating the factor V Leiden or prothrombin G20210A mutations or fibrinogen G−455A or plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphisms with the risk of myocardial infarction. Studies were included only if they used solid diagnostic criteria and complied with published methodological criteria. A common OR with corresponding 95% CI was calculated for the risk of myocardial infarction in a fixed-effect model according to Mantel-Haenszel. The factor V Leiden and prothrombin G20201A mutations did not significantly correlate with myocardial infarction (OR 1.26, 95% CI 0.94 to 1.67, P =0.12 and OR 0.89, 95% CI 0.59 to 1.35, P =0.6, respectively). Inclusion of the studies that investigated young patients (P =0.02). Homozygosity for the fibrinogen −455A allele was significantly associated with a decreased risk of myocardial infarction (OR 0.66, 95% CI 0.44 to 0.99, P =0.04), whereas the PAI-1 4G4G genotype was significantly associated with increased risk (OR 1.20, 95% CI 1.04 to 1.39, P =0.04). Conclusions — Associations between these genetic variations and myocardial infarction were weak or absent. In the absence of clinical implications, our results indicate that screening of patients with myocardial infarction for these genetic variations is not warranted.

Matthijs Boekholdt and John Kastelein state in their Comment (Jan 9, p 95) that measurement of C-reactive protein (CRP) might be useful in identifying individuals at risk of cardiovascular disease, but the large meta-analysis by the Emerging Risk Factors Collaboration (recording 28 000 cardiovascular disease events) indicates otherwise. The risk ratio for coronary heart disease between individuals with CRP in the upper and lower quintile groups (fifths) of the distribution was about 2·5, which translates to an expected detection rate (sensitivity) of about 10% for a 5% false-positive rate. This is poor discrimination, little better than selecting people for preventive treat ment at random. The figure shows detection rate plotted against false-positive rate for CRP and first coronary heart disease events, based on a published meta-analysis of 22 cohort stud ies. The plot barely deviates from the diagonal line (indicating a useless screening test) and the data confirm that the detection rate is only 11% for a 5% false-positive rate. The same con clusion was reached independently by Hingorani and col leagues, and holds even if CRP is used with other risk factors. Boekholdt and Kastelein also suggest that CRP may be useful in quantifying the efficacy of interventions for cardio vascular disease prevention, but this is unlikely because CRP is too nonspecific, being raised in many conditions (eg, cancer and lung disease) as the meta-analysis by the Emerging Risk Factors Collaboration shows. The available evidence shows that CRP measurement has no Authors’ reply We do not agree with David Wald and Jonathan Bestwick’s interpretation of the clinical relevance of C-reactive protein (CRP) for several reasons. First, it remains unclear to us which statistical criteria they used to support their interpretation that the observed detection rates are clinically irrelevant. In fact, we do not agree that lack of statistical significance always implies lack of clinical relevance. Second, eFigure 5 (webappendix, p 18) of the Emerging Risk Factors Collaboration meta-analysis shows that the association with risk of coronary heart disease is at least as strong for CRP as it is for total cholesterol, non-HDL cholesterol, and systolic blood pressure. Following Wald and Bestwick’s reasoning, this would entail that cholesterol measures and blood pressure are useless risk factors as well and have no practical value in cardiovascular disease management—a verdict few would agree with. 0 0 10 20 30 40 50 60

The Authors’ reply , We were intrigued by the comments from Meune et al 1 on our article on treatment decisions based on hybrid single photon emission computed tomography (SPECT) and coronary computed tomography angiography (CCTA) for patients with stable anginal complaints.2 Prognosis and relief of anginal complaints determine the treatment strategy for each individual patient with coronary artery disease (CAD).3 In patients with high-risk CAD (two-vessel disease (VD) involving the left anterior descending, three-VD or left …

Context The associations of low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B (apoB) levels with the risk of cardiovascular events among patients treated with statin therapy have not been reliably documented. Objective To evaluate the relative strength of the associations of LDL-C, non-HDL-C, and apoB with cardiovascular risk among patients treated with statin therapy. Design Meta-analysis of individual patient data from randomized controlled statin trials in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. Data Sources Relevant trials were identified by a literature search updated through December 31, 2011. Investigators were contacted and individual patient data were requested and obtained for 62154 patients enrolled in 8 trials published between 1994 and 2008. Data Extraction Hazard ratios (HRs) and corresponding 95% CIs for risk of major cardiovascular events adjusted for established risk factors by 1-SD increase in LDL-C, non-HDL-C, and apoB. Results Among 38 153 patients allocated to statin therapy, 158 fatal myocardial infarctions, 1678 nonfatal myocardial infarctions, 615 fatal events from other coronary artery disease, 2806 hospitalizations for unstable angina, and 1029 fatal or nonfatal strokes occurred during follow-up. The adjusted HRs for major cardiovascular events per 1-SD increase were 1.13 (95% CI, 1.10-1.17) for LDL-C, 1.16 (95% CI, 1.12-1.19) for non-HDL-C, and 1.14 (95% CI, 1.11-1.18) for apoB. These HRs were significantly higher for non-HDL-C than LDL-C (P=.002) and apoB (P=.02). There was no significant difference between apoB and LDL-C (P=.21). Conclusion Among statin-treated patients, on-treatment levels of LDL-C, non-HDL-C, and apoB were each associated with risk of future major cardiovascular events, but the strength of this association was greater for non-HDL-C than for LDL-C and apoB. JAMA. 2012;307(12):1302-1309 www.jama.com

Objective— Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. Methods and Results— We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10 −8 to 3.1×10 −10 ). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2 , APOB , APOE-C1-C4-C2 cluster, LPL , ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1×10 −3 to 1.2×10 −9 ). Conclusion— We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.

Background There is a continuous relationship between glycated hemoglobin (HbA 1c ) and coronary heart disease (CHD) risk, even below diagnostic thresholds for diabetes mellitus. Methods To evaluate the Framingham risk score in a UK population-based prospective cohort (European Prospective Investigation of Cancer [EPIC]–Norfolk) and to assess whether adding HbA 1c improves the prediction of CHD. Participants aged 40 to 79 years were recruited from UK general practices, attended a health check, and were followed up for CHD events and death. The Framingham risk score was computed for 10 295 individuals with data on age, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, diabetes mellitus, and smoking status. We developed a Cox proportional hazards regression model with the original Framingham covariates and then added HbA 1c to determine whether this improved the prediction of CHD. Model discrimination was compared by using area under the receiver operating characteristic curves (AUROCs), and the correctness of reclassification was determined by calculating the net reclassification improvement and the integrated discrimination improvement. The main outcome measures were CHD-related hospital admission and death. Results A total of 430 men and 250 women developed CHD during 8.5 years of follow-up. The AUROC for the original Framingham risk score was 0.71. Using the Framingham variables with coefficients fitted from the EPIC-Norfolk data, the AUROC was 0.72 for men and 0.80 for women, compared with 0.73 and 0.80, respectively, in a score including HbA 1c . This difference was significant for men only ( P = .005). The net reclassification improvement was 3.4% ( P = .06) in men and −2.2% ( P = .27) in women. Conclusions The Framingham risk score predicts CHD in this cohort. The addition of HbA 1c made a small but statistically significant improvement to discrimination in men but not in women, without significant improvement in reclassification of risk category.